Tuberculosis (TB) is a leading cause of infectious disease death, especially in HIV-prevalent regions, and the emergence of highly resistant TB further threatens global TB control. There is a need for highly potent TB treatments that can cure disease in substantially fewer than the six months currently required. PA-824, an investigational nitroimidazole with bactericidal and sterilizing activity against Mycobacterium tuberculosis (M. tuberculosis), has potential as a treatment-shortening drug when used as part of multidrug TB therapy. In an experimental murine model of TB, PA-824 was shown to have bactericidal activity during the early phase of TB treatment and sterilizing activity during the continuation phase of TB therapy when given as monotherapy. In subsequent murine studies, using PA-824 in combination with a multidrug regimen containing rifampin and pyrazinamide reduced the treatment time required for cure from six months to four months. The applicant reported that Phase 1 and early Phase 2 studies suggest that PA-824 is well tolerated and has measurable, dose-dependent early bactericidal activity, reducing sputum colony counts of M. tuberculosis over two weeks of once-daily dosing. The main objective of the proposed Phase 2 clinical trial is to evaluate the antimicrobial activity of PA-824 when added to standard-dose TB treatment over the first 12 weeks of TB treatment. Patients with sputum smear-positive pulmonary TB in Cape Town, South Africa, will receive standard doses of isoniazid, rifampin, and pyrazinamide and will be randomized to receive PA-824 200 mg once daily for 8 weeks (Arm 1), PA-824 200 mg once daily for 12 weeks (Arm 2), or ethambutol at standard doses for 8 weeks (control arm). The primary efficacy endpoint will be time to stable sputum culture conversion in liquid media, defined as the time from the start of treatment until the first of at least two negative sputum cultures, over 12 weeks. The primary safety endpoint is grade 3 or higher adverse events. Pharmacokinetics, solid culture results after 8 weeks of treatment, change in time to sputum culture positivity in liquid culture, and quantitative change in extent of disease on computed tomography will also be assessed. Results will determine the antimicrobial activity of daily PA-824 and inform further development of PA-824.